5,6-dihydropyrimidin-4(3h)one derivatives, and antiedema compositions and methods employing them

ABSTRACT

An antiedema compound of the formula: ##STR1## in which R 1  is methyl, ethyl, cyclohexyl, phenyl, m-tolyl, p-tolyl, p-tert-butylphenyl, m-trifluoromethylphenyl, m-fluorophenyl, p-fluorophenyl, m-chlorophenyl, p-chlorophenyl, m-bromophenyl, p-bromophenyl, o-hydroxyphenyl, p-methoxyphenyl, p-nitrophenyl, benzyl, p-chlorobenzyl, m,p-dimethoxybenzyl, and o-pyridyl; 
     R 2  is hydrogen, p-tolyl, p-ethoxyphenyl, m-pyridyl, methyl or phenyl; and 
     n is 1, 2 or 3 
     And a process for the preparation thereof are disclosed.

The present invention relates to new cis- and trans-5,6-alkylene-5,6-dihydro-pyrimidin-4(3H)-on derivatives of the formula I ##STR2## wherein R¹ stands for a lower alkyl, aryl, substituted aryl, aralkyl, or heteroaryl group,

R² stands for a hydrogen atom, or an alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl or heteroaryl group,

n = 1, 2 or 3.

According to an other aspect of the invention there is provided a method for the preparation of the compounds of the formula I, wherein R¹ and R² have the same meaning as defined above, which comprises reacting 2-aminocycloalkane-carboxylic acid derivatives of the formula II ##STR3## wherein R³ stands for a hydroxyl, alkoxy or --NH--R² group, wherein R² has the same meaning as defined above,

R⁴ stands for a hydrogen atom, or a ##STR4## group, WHEREIN

R¹ has the same meaning as defined above,

n has the same meaning as defined above with compounds of the formula III

    a -- b                                                     (iii)

wherein

A stands for a hydrogen atom, an alkoxy or amino group, or a halogen atom,

B represents an --NH--R², ##STR5## group R⁵ stands for an alkyl or aryl group, and

R⁶ represents a hydrogen atom, an alkyl or aryl group.

There are only a few 5,6-alkylene-5,6-dihydropyrimidin-4(3H)-on derivatives already published. The basic compounds were described by Armarego and Kobayashi in J. Chem. Soc. 1969, 1635 and J. Chem Soc. (C) 1971, 238. The authors prepared, however, the unsubstituted derivatives of tetramethylene-pyrimidin-4(3H)-ons nominated as 4a,5,6,7,8,8a-hexahydroquinazoline-4(3H)-on only, and the pharmacological activity of those compounds has not been even mentioned. It should be noted that the aromatic 4(3H)-on-quinazoline derivatives closely related with the above compounds possess narcotic and anticonvulsive properties. (J. Indian Chem. Soc. 26, 344 (1951), J. Pharmacy and Pharmacology 12, 501 (1960). The 2- and 2- and 3-substituted, 5,6-alkylene-5,6-dihydro-pyrimidin-4(3H)-on derivatives provided by the invention show outstanding antiinflammatory, antifebrile, analgesic and narcosis potentiating activity.

According to a preferred embodiment of the process provided by the invention 2-amino-1-cycloalkane-carboxylic acids of the formula II are reacted with alkyl- or aryl-imidates of the formula III. The imidates may be substituted or unsubstituted as well. In case that they are substituted, i.e. R⁶ is other than hydrogen, 3-substituted 5,6-alkylene-5,6-dihydro-pyrimidin-4(3H)-on derivatives are obtained. The reaction is carried out preferably in a suitable solvent, with heating. As solvent reaction-inert solvents, for example aromatic hydrocarbons, substituted aromatic hydrocarbons, ethers may be applied. An especially preferred solvent is chlorobenzene. The reaction may be accomplished at a temperature between 20° C. and 150° C. The reaction time may vary depending upon the reaction temperature and is between 4 and 30 hours. The progress of the reaction may be controlled by t.l.c. When the reaction is complete the reaction mixture is evaporated and the residue optionally is purified by recrystallization.

According to another embodiment of our process 2-amino-1-cycloalkanecarboxamides of the formula II are reacted with orthoacid-esters of the formula III under the conditions described above. In this case, if the carboxamide is N-substituted, 3-substituted pyrimidine derivatives are prepared.

According to a still further embodiment of our process 2-amino-1-cycloalkanecarboxamides of the formula II are reacted with amidines of the formula III. The reaction is preferably carried out in such a manner that to the mixture of 2-amino-1-cycloalkane-carboxylic acid and a salt of the amidine a calculated amount of alkali- and alkali earth-alcoholate is added in order to deliberate amidin base, and thereafter -- if necessary -- the reaction is promoted by heating. The reaction mixture is filtered hot and the product is obtained by crystallization of the mixture.

One can proceed also by reacting an ester of 2-amino-1-cycloalkane-carboxylic acid with N,N-dimethyl-formamide-chloride and thus preparing N,N-dimethyl-N-[2-(ethoxy-carbonyl)-cyclohexyl]-formamidine hydrochloride. The reaction is carried out preferably in a solvent.

Examples of suitable solvents are aliphatic and aromatic hydrocarbons, halogenated hydrocarbons and ethers. The reaction temperature is between 0° C. and 60° C., and the product is obtained by evaporating the mixture and may be purified by recrystallization. Reacting the thus obtained N,N-dimethyl-N-[2-(ethoxy-carbonyl)-cycloalkyl]-formamidine with ammonia or amines the 5,6-alkylene-5,6-dihydropyrimidin-4(3H)-on derivatives are obtained. During the reaction the reacting amine replaces the dimethylamine split off, whereupon the resulted new formamidine derivative reacts with the vicinal ethoxy-carbonyl group. The ring closure reaction results in the formation of a 5,6-alkylene-5,6-dihydropyrimidin-4(3H)-on derivative and alcohol. The reaction can be effected in dioxane but also other reaction-inert solvents, for example other ethers, hydrocarbons, chlorinated hydrocarbons etc. may be used. The ammonium salts and substituted ammonium salts precipitating during the reaction are filtered off, and the product is obtained by evaporating the reaction mixture and may be purified, if necessary, by various physical methods. A very effective purification method is for example thin layer chromatography.

The above reactions may be effected with the same results using cis- or trans-2-amino-1-cycloalkane-carboxylic acids or their derivatives, but the mixture of the cis- and trans-compounds may be also applied. Further details of our invention are illustrated with the following Examples without limiting the scope of the invention to the Examples.

EXAMPLE 1

Cis- or trans-2-amino-1-cyclohexane-carboxylic acid (0.01 mole) is suspended in chlorobenzene (20 ml) and an ethylimidate derivative (0.012 mole) is added. The reaction mixture is refluxed and the progress of the reaction is followed by thin layer chromatography (silica-gel -- benzene -- ethanol 4:1). When the reaction is completed (about 15 to 20 hours) the mixture is evaporated under reduced pressure and the residue is crystallized. The characteristics of the thus obtained 2-substituted cis- and trans-4a,5,6,7,8,8a-hexahydroquinazoline-4(3H)-ons are listed in Table 1.

                                      Table 1                                      __________________________________________________________________________      ##STR6##                                                                      Melting point and analysis data for 2-substituted 4a,5,6,7,8,8a-hexahydroq     uinazolin-4(3H)-on (I)                                                                                 M.p. ° C.                                                                       Analysis                                                       Formula for the solvent                                                                        calculated                                               Configura-                                                                           molar   used for                                                                               found (%)                                                                               Yield                                 R.sup.1   tion  weight  crystallisation                                                                        C  H  N  %   Remark                            __________________________________________________________________________     methyl    cis   C.sub.9 H.sub.14 N.sub.2 O                                                             146-148 64.99                                                                             8.47                                                                              16.85                                                                             51.31                                                                              From cis-amide                                    166.22  sublimated                                                                             64.70                                                                             8.78                                                                              16.70  with ortho-                                                                    esther                            cyclohexyl                                                                               cis   C.sub.14 H.sub.22 N.sub.2 O                                                            158     71.75                                                                             9.46                                                                              11.96                                                                             21.80                                                                              when prepared vom                                 234.33  ether   71.96                                                                             9.67                                                                              11.63  cis-acid, mixture                                                              may be separated                                                               from ether by                                                                  crystallization                   phenyl    cis   C.sub.14 H.sub.16 N.sub.2 O                                                            186-187 73.65                                                                             7.02                                                                              12.28                                                                             84.21                                                                              JATE 57                                           228.29  chlorobenzene                                                                          73.20                                                                             7.06                                                                              12.01                                    phenyl    trans C.sub.14 H.sub.16 N.sub.2 O                                                            207-209 73.65                                                                             7.02                                                                              12.28                                                                             67.21                                                                              JATE 58                                           228.29  chlorobenzene                                                                          73.89                                                                             6.95                                                                              12.47                                    m-tolyl   cis   C.sub.15 H.sub.18 N.sub.2 O                                                            146-148 74.35                                                                             7.49                                                                              11.56                                                                             69.29                                                                              JATE 118                                          242.31  chlorobenzene                                                                          74.41                                                                             7.79                                                                              11.67                                    p-tolyl   cis   C.sub.15 H.sub.18 N.sub.2 O                                                            171-173 74.35                                                                             7.49  73.21                                                                              JATE 122                                          242.31  chlorobenzene                                                                          74.50                                                                             7.89      from cis-amino                                                                 acid                              p-tolyl   trans C.sub.15 H.sub.18 N.sub.2 O                                                            222     74.35                                                                             7.49                                                                              11.56                                                                             75.67                                                                              JATE 111                                          242.31  chlorobenzene                                                                          74.69                                                                             7.89                                                                              11.58                                    p-tert.   trans C.sub.18 H.sub.24 N.sub.2 O                                                            230-231 76.02                                                                             8.45                                                                              9.85                                                                              87.36                                                                              JATE 110                          butylphenyl     284.40  chlorobenzene                                                                          76.40                                                                             8.32                                                                              10.51                                    m-trifluoromethyl-                                                                             C.sub.15 H.sub.15 F.sub.3 N.sub.2 O                                                    164-165 60.81                                                                             5.10                                                                              9.46                                                                              71.32                                                                              JATE 161                          phenyl          296.29  ethanol 60.56                                                                             5.20                                                                              9.35   from cis-amino                                                                 acid                              m-fluorophenyl                                                                           cis   C.sub.14 H.sub.15 FN.sub.2 O                                                           120-123 68.27                                                                             6.14                                                                              11.37                                                                             78.71                                                                              JATE 117                                          246.29  chlorobenzene                                                                          68.41                                                                             6.43                                                                              10.88                                    m-fluorophenyl                                                                           trans C.sub.14 H.sub.15 FN.sub.2 O                                                           213     68.27                                                                             6.14                                                                              11.37                                                                             79.73                                                                              JATE 104                                          246.29  ethanol 68.20                                                                             6.29                                                                              11.76                                    p-fluorophenyl                                                                           cis   C.sub.14 H.sub.15 FN.sub.2 O                                                           191-193 68.27                                                                             6.14                                                                              11.37                                                                             78.47                                                                              JATE 103                                          246.29  chlorobenzene                                                                          68.75                                                                             6.50                                                                              10.95                                    p-fluorophenyl                                                                           trans C.sub.14 H.sub.15 FN.sub.2 O                                                           233     68.27                                                                             6.14                                                                              11.37                                                                             50.00                                                 246.29  ethanol 68.16                                                                             6.24                                                                              12.15                                    m-chlorophenyl                                                                           cis   C.sub.14 H.sub.15 ClN.sub.2 O                                                          162-164 64.01                                                                             5.76                                                                              10.66                                                                             71.30                                                                              JATE 105                                          262.74  chlorobenzene                                                                          63.66                                                                             5.89                                                                              10.95                                    p-chlorophenyl                                                                           trans C.sub.14 H.sub.15 ClN.sub.2 O                                                          211     64.01                                                                             5.76                                                                              10.66                                                                             74.15                                                                              JATE 106                                          262.74  ethanol 64.22                                                                             6.10                                                                              11.26                                    p-chlorophenyl  C.sub.14 H.sub.15 ClN.sub.2 O                                                          178-181 64.01                                                                             5.76                                                                              10.66                                                                             68.98                                                                              JATE 83                                           262.74  ethanol 64.25                                                                             5.77                                                                              10.46  from cis                                                                       amino acid                        p-chlorophenyl  C.sub.14 H.sub.15 ClN.sub.2 O                                                          247-249 64.00                                                                             5.75                                                                              10.65                                                                             64.05                                                                              JATE 84                                           262.74  chlorobenzene                                                                          64.70                                                                             5.85                                                                              10.90  from trans                                                                     amino acid                        m-bromophenyl   C.sub.14 H.sub.15 BrN.sub.2 O                                                          167-170 54.74                                                                             4.92                                                                              9.12                                                                              79.27                                                                              JATE 107                                          307.20  ethanol 54.56                                                                             4.93                                                                              9.46   from cis                                                                       amino acid                        m-bromophenyl                                                                            trans C.sub.14 H.sub.15 BrN.sub.2 O                                                          206-207 54.74                                                                             4.92                                                                              9.12                                                                              64.21                                                                              JATE 108                                          307.20  ethanol 54.72                                                                             5.11                                                                              9.11                                     p-bromophenyl                                                                            cis   C.sub.14 H.sub.15 BrN.sub.2 O                                                          188-193 54.74                                                                             4.92                                                                              9.12                                                                              82.37                                                 307.20  chlorobenzene                                                                          55.17                                                                             4.89                                                                              9.12                                     p-bromophenyl   C.sub.14 H.sub.15 BrN.sub.2 O                                                          252-253 54.74                                                                             4.92                                                                              9.12                                                                              69.73                                                 307.20  chlorobenzene                                                                          54.82                                                                             5.14                                                                              9.03   from trans                                                                     amino acid                        o-hydroxyphenyl C.sub.14 H.sub.16 N.sub.2 O.sub.2                                                      217-220 68.83                                                                             6.60                                                                              11.47                                                                             67.23                                                 244.28  ethanol 68.54                                                                             6.82                                                                              12.06                                    p-methoxyphenyl C.sub.15 H.sub.18 N.sub.2 O.sub.2                                                      189-191 69.75                                                                             7.03                                                                              10.85                                                                             81.26                                                 258.32  ethanol 70.01                                                                             7.09                                                                              10.67                                    p-methoxyphenyl                                                                          trans C.sub.15 H.sub.18 N.sub.2 O.sub.2                                                      188-190 69.75                                                                             7.03                                                                              10.85                                                                             71.27                                                 258.32  chlorobenzene                                                                          68.82                                                                             7.38                                                                              10.86                                    p-nitrophenyl   C.sub.14 H.sub.15 N.sub.3 O.sub.3                                                      202-204 61.53                                                                             5.53                                                                              15.38                                                                             52.15                                                 273.29  ethanol 61.41                                                                             5.70                                                                              15.06  from cis                                                                       amino acid                        p-nitrophenyl   C.sub.14 H.sub.15 N.sub.3 O.sub.3                                                      247-250 61.53                                                                             5.53                                                                              15.38                                                                             34.17                                                 273.29  benzene 61.47                                                                             5.83                                                                              15.32  from trans                                                                     amino acid                        benzyl    trans C.sub.15 H.sub.18 N.sub.2 O                                                            149-151 74.40                                                                             7.43                                                                              11.57                                                                             42.47                                                 242.32  benzene 74.38                                                                             7.71                                                                              11.60  from cis                                                                       amino acid                                                                     in ether                                                                       fractionated                                                                   cryst.                            p-chlorobenzyl                                                                           cis   C.sub.15 H.sub.17 ClN.sub.2 O                                                          133-135 65.09                                                                             6.19                                                                              10.12                                                                             51.30                                                 276.77  ethanol-ether                                                                          65.00                                                                             6.46                                                                              10.05  from cis                                                                       amino acid                        m,p-dimethoxy-                                                                           trans C.sub.17 H.sub.22 N.sub.2 O.sub.3                                                      135-137 67.54                                                                             7.28                                                                              9.27                                                                              27.9                                                                               from cis                          benzyl          302.38  benzene 67.60                                                                             7.17                                                                              9.19   amino acid                                                                     in ether                                                                       fractionated                                                                   cryst. -o-pyridyl  C.sub.14                                                    H.sub.15 N.sub.3 O 101-103 69                                                  .69 6.27 17.42 37.40 from                                                      trans                                             241.29  ether   69.13                                                                             6.81                                                                              17.43  amino acid                        __________________________________________________________________________

EXAMPLE 2

Following the procedure of Example 1, reacting cis- or trans-2-amino-1-cycloheptane-carboxylic acid (0.01 mole) in chlorobenzene (20 ml.) with an ethylimidate derivative (0.012 mole) cis- and trans-5,6-pentamethylene-5,6-dihydropyrimidine-4(3H)-on derivatives listed in table 2 are obtained.

                                      Table 2                                      __________________________________________________________________________      ##STR7##                                                                      Melting point and analysis data for 2-substituted trans-5,6-pentamethylene     5,6-dihydropyrimidine-4(3H)-on                                                                       M.p. ° C.                                                                       Analysis                                                               for the solvent                                                                        Calculated                                                      Formula                                                                               used for                                                                               found    Yield                                   R.sup.1 Configuration                                                                         molar weight                                                                          crystallization                                                                        C: H: N: %   Remarks                             __________________________________________________________________________     phenyl  cis    C.sub.15 H.sub.18 N.sub.2 O                                                           145-146 74.40                                                                             7.44                                                                              11.56                                                                             65.17                                                  242.32 ethanol 73.68                                                                             7.36                                          phenyl  trans  C.sub.15 H.sub.18 N.sub.2 O                                                           180-183 74.40                                                                             7.44                                                                              11.56                                                                             42.51                                                  242.32 ethanol 74.40                                                                             7.55                                          p-tert-butyl-  C.sub.19 H.sub.26 N.sub.2 O                                                           193-197 76.51                                                                             8.72                                                                              9.32                                                                              37.15                                                                              from trans                          phenyl         298.36 benzene 76.60                                                                             9.09                                                                              9.66   amino acid                          m-chlorophenyl C.sub.15 H.sub.17 ClN.sub.2 O                                                         187-195 65.08                                                                             6.19                                                                              10.12                                                                             33.50                                                                              from trans                                         276.77 ethanol 65.02                                                                             6.24                                                                              9.92   amino acid                          p-chlorophenyl C.sub.15 H.sub.17 ClN.sub.2 O                                                         208-209 65.08                                                                             6.19                                                                              10.12                                                                             41.15                                                                              from trans                                         276.77 ethanol 65.29                                                                             5.85                                                                              10.57  amino acid                          p-bromophenyl  C.sub.15 H.sub.17 BrN.sub.2 O                                                         236     55.94                                                                             5.63                                                                              8.70                                                                              68.10                                                                              JATE 88                                            321.23 chlorobenzene                                                                          55.61                                                                             5.37                                                                              8.74   from trans                                                                     amino acid                          p-nitrophenyl  C.sub.15 H.sub.17 N.sub.3 O.sub.3                                                     240-243 62.71                                                                             5.96                                                                              14.62                                                                             38.20                                                                              JATE 90                                            287.32 chlorobenzene                                                                          62.66                                                                             6.15                                                                              14.51  from trans                                                                     amino acid                          __________________________________________________________________________

TABLE 3

Following the procedure of Example 1, with the reaction of cis- or trans-2-amino-1-cyclohexane-carboxylic acid (0.01 mole) in 20 ml. of chlorobenzene with N-substituted-ethylimidate the cis- and trans-2,3-disubstituted-4a,5,6,7,8,8a-hexahydroquinazoline-4(3H)-on derivatives listed in table 3 are obtained.

                                      Table 3                                      __________________________________________________________________________      ##STR8##                                                                      Melting point and analysis data for 2,3-disubstituted 4a,5,6,7,8,8a-           hexahydroquinazoline-4(3H)-one (III)                                                                   M.p. ° C.                                                                       Analysis                                                               for the solvent                                                                        calculated                                                      Formula                                                                               used for                                                                               found    Yield                                 R.sup.1                                                                            R.sup.2                                                                              Configuration                                                                         molar weight                                                                          crystallization                                                                        C: H: N: %    Remark                           __________________________________________________________________________     methyl                                                                             p-tolyl                                                                              cis    C.sub.16 H.sub.20 N.sub.2 O                                                           71-74   74.96                                                                             7.86                                                                              10.93                                                                             37.15                                                                               JATE 169                                          265.34 n-hexane                                                                               75.13                                                                             8.09                                                                              10.63   from acid                                                                      amide with                                                                     o-acid-ester                     methyl                                                                             p-ethoxy-    C.sub.17 H.sub.22 N.sub.2 O.sub.2                                                     179-180 71.30                                                                             7.74                                                                              9.78                                                                              32.21                                                                               JATE 170                             phenyl       286.36 ethanol 71.03                                                                             7.46                                                                              9.94    from acid                                                                      amide with                                                                     o-acid-ester                     methyl                                                                             p-ethoxy-    C.sub.17 H.sub.22 N.sub.2 O.sub.2                                                     94-97   71.30                                                                             7.74  14.27                                                                               from cis-                            phenyl       286.36 ether-petroleum                                                                        70.54                                                                             7.56       aminoacid                                                ether                 with imino-                                                                    ether                            methyl                                                                             p-ethoxy     C.sub.17 H.sub.22 N.sub.2 O.sub.2                                                     177-178 71.30                                                                             7.74  10.35                                                                               from cis-                            phenyl       286.36 ether                 aminoacid                                                                      with imino-                                                                    ether                            ethyl                                                                              m-pyridyl    C.sub.14 H.sub.17 N.sub.3 O                                                           115-118 69.11                                                                             7.04                                                                              17.27                                                                             31.17                                                                               from acid-                                        243.30 diisopropylether                                                                       68.64                                                                             7.03                                                                              16.66   amide with                                                                     o-acid-                                                                        esther                           ethyl                                                                              p-tolyl      C.sub.17 H.sub.22 N.sub.2 O                                                           63-66   75.52                                                                             8.20                                                                              10.36                                                                             33.27                                                                               from acid                                         270.36 n-hexane                                                                               75-57                                                                             8.42                                                                              10.64   amide with                                                                     o-acid-                                                                        ester                            phenyl                                                                             methyl                                                                               cis    C.sub.15 H.sub.18 N.sub.2 O                                                           80-82   74.36                                                                             7.49                                                                              11.56                                                                             21.51                                                                               from cis-                                         242.32 ether   74.80                                                                             7.39                                                                              11.27   with imino-                                                                    ether                            phenyl                                                                             p-tolyl      C.sub.21 H.sub.22 N.sub.2 O                                                           200-203 79.21                                                                             6.96                                                                              8.80                                                                              34.35                                                                               from acid                                         318.40 ethylacetate                                                                           79.56                                                                             7.34                                                                              8.63    amide with                                                                     o-acid-                                                                        ester                            phenyl                                                                             phenyl       C.sub.20 H.sub.20 N.sub.2 O                                                           180-182 78.92                                                                             6.62                                                                              9.20                                                                              20.13                                                                               from cis-                                         304.39 ether   78.54                                                                             6.27                                                                              9.20    aminoacid                                                                      with imino-                                                                    ether                            __________________________________________________________________________

EXAMPLE 4

N-substituted 2-amino-1-cyclohexane-carboxamide (0.01 mole) is suspended in chlorobenzene (25 ml.) and boiled with orthoacid ester (0.011 mole) for 8 to 10 hours. The chlorobenzene is distilled off under reduced pressure and the residue is crystallized. The thus obtained 2,3-disubstituted 4a,5,6,7,8,8a-hexahydro-quinazoline-4(3H)-on derivatives were set forth in table 3.

EXAMPLE 5

cis-2-Amino-1-cyclopentane-carboxylic acid (12.92 g., 0.1 mole) is boiled with ethylbenzimidate (16.41 g., 0.11 mole) for 20 hours according to the procedure of Example 1. Thus 14.1 g. of 2-phenyl-cis-5,6-trimethylene-5,6-dihydropyrimidine-4-(3H)-on are obtained. Melting point after recrystallization from ethanol: 130° C. to 140° C.

Analysis for C₁₅ H₁₂ N₂ O; Calculated: C 72.86% H 6.59% N 13.07%; Found: C 73.43% H 6.74% N 13.13%.

EXAMPLE 6

cis-2-Amino-1-cyclohexane-carboxylic acid (1 g., 0.005 mole) and p-methoxy-benzamidine-hydrochloride (1.3 g., 0.005 mole) are suspended in chlorobenzene (50 ml.). To the suspension sodium ethylate (0.4 g., 0.005 mole) is added and then mixture is boiled for 20 hours. Thereafter the resulted sodium chloride and the unreacted amino-acid component are filtered off hot. At 0° C. 2-(p-methoxy-phenyl)-cis-4a,5,6,7,8,8a-hexahydroquinazoline-4(3H)-on precipitates, which is filtered off and crystallized from benzene until its melting point is constant.

Yield: 0.8 g., melting point: 188°-191° C.

Analysis for C₁₅ H₁₈ N₂ O₂ ; Calculated: C 69.75% H 7.03% N 10.85%; Found: C 69.91% H 7.11% N 10.68%.

EXAMPLE 7

To the mixture of N,N-dimethyl-formamidechloride (12.99 g., 0.01015 mole) and abs. chloroform (20 ml.) ethyl-(cis-2-amino-1-cyclohexanecarboxylate) (14.32 g., 0.1 mole) in 40 ml. of abs. chloroform is added dropwise, assuring that the reaction temperature does not exceed 40° C. Thereafter chloroform is distilled off and the residue is crystallized from dioxane. 22.38 g. of white, hygroscopic N,N-dimethyl-N-cis-2 -(ethoxy-carbonyl)-cyclohexyl-formamidine-hydrochloride are obtained.

Melting point: 137° C. to 142° C.

Analysis for C₁₂ H₂₃ ClN₂ O; Calculated: C 54.84% H 8.82% N 10.66% Cl 13.4%; Found: C 54.38% H 8.94% N 11.08% Cl 13.55%.

The melting point of the picrate is: 114° C. to 116° C.

Analysis for C₁₈ H₂₅ N₅ O₉ ; Calculated: C 47.48% H 5.53% N 15.38%; Found: C 47.51% H 5.78% N 15.31%.

EXAMPLE 8

N,N-Dimethyl-N-cis-2-(ethoxy-carbonyl)-cyclohexenyl-formamidine-hydrochloride (1 g. 0.0038 mole) is suspended in abs. dioxane (20 ml.) and dry ammonia-gas is introduced into the mixture within 1.5 hours. The precipitated ammoniumchloride is filtered off, and the solution is evaporated to dryness. The dry residue is dissolved in chloroform and separated from the starting material on silicagel thin layer, with 8 : 2 petrolether -- chloroform solvent mixture by chromatography. The hexahydroquinazoline spot is scratched from the layer and the substance is dissolved with chloroform. Thus 0.2 g. of cis-4a,5,6,7,8,8a-hexahydroquinazoline-4(3H)-on, melting at 133° to 134° C. are obtained.

Analysis for C₈ H₁₂ N₂ O; Calculated: C 63.13% H 7.95% N 18.41%; Found: C 63.11% H 7.84% N 18.31%.

3-(p-tolyl)-4a,5,6,7,8,8a-hexahydroquinazoline-4(3H)-on

N-p-tolyl-cis-2-amino-1-cyclohexane-carboxanilide (0.01 mole, 2.32 g.) is dissolved in chlorobenzene (40 ml.) and the solution, after the addition of ethyl-o-formiate (1.63 g.) is refluxed for 6 hours. The solvent is distilled off under reduced pressure. The residue is crystallized from petroleum ether. Thus a white, crystalline product, melting at 79° C. to 82° C. is obtained.

Yield: 1.25 g. (51.51%).

Analysis for C₁₅ H₁₈ N₂ O (242.32); Calculated: C 74.35% H 7.49% N 11.56%; Found: C 73.93% H 7.43% N 11.76%.

2-Phenyl-4a,5,6,7,8,8a-hexahydroquinazoline-4(3H)-on

N-butyl- or N-phenyl-cis-2-amino-1-cyclohexane-carboxamide (0.01 mole) is dissolved in 40 ml. chlorobenzene and after the addition of ethyl-phenyl-imidate (0.011 mole) the solution is refluxed for 50 hours. The solvent is distilled off under reduced pressure (2.5 Hgmm.) and the residue is crystallized from the below-identified solvents.

(a) Starting substance: N-butyl-cis-2-amino-1-cyclohexane-carboxamide

Product: White crystalline solid, melting 165° C. to 167° C. (from ethanol)

Yield: 73.81%

Analysis for C₁₄ H₁₆ N₂ O (228.30) Calculated: C 73.65% H 7.02% N 12.28%; Found: C 73.25% H 7.05% N 12.15%.

(b) Starting substance: N-phenyl-cis-2-amino-1 -cyclohexane-carboxanilide.

Product: white, crystalline compound, melting at 165° C. to 168° C. (ethanol)

Yield: 69.65%

Analysis for C₁₄ H₁₆ N₂ O (228.30); Calculated: C 73.65% H 7.02% N 12.28%; Found: C 73.65% H 7.28% N 11.79%.

(c) Starting substance: cis-2-amino-1-cyclohexanecarboxamide

Product: white, crystalline compound, melting at 168° C. to 170° C. (ethanol).

Yield: 65.27%.

Analysis for C₁₄ H₁₆ N₂ O (228.30); Calculated: C 73.65% H 7.02% N 12.28%; Found: C 73.22% H 7.20% N 11.99%.

2-Phenyl-3-methyl-4a,5,6,7,8,8a-hexahydroquinazoline-4(3H)-on

N-Methyl-benzamide-imidachloride (0.01 mole) is dissolved in abs. acetone (20 ml.) and ethyl-hexahydroantranilate (0.02 mole) in acetone (40 ml.) is added dropwise, at 0° C. The mixture is allowed to stand at room temperature overnight, whereupon the acetone is distilled off. The base is set free on a Varion AD anion-exchanger, and the unreacted ester is distilled off under reduced pressure (2.5 Hgmm.). The residue is crystallized from petroleum ether. Melting point: 79°-82° C., yield: 38.25%.

Analysis for C₁₅ H₁₈ N₂ Oj (242.32); Calculated: C 74.36% H 7.49% N 11.56%; Found: C 74.68% H 7.38% N 11.32%.

2-(m-chlorophenyl)-cis-5,6-trimethylene-5,6-dihydro-pyrimidine-4(3H)-on

Following the procedure of Example 1, cis-2-amino-1-cyclopentane-carboxylic acid (12.92 g.) is boiled with ethyl-m-chloro-benzimidate (20.2 g.) for 20 hours. 17 g. of 2-(m-chlorophenyl)-cis-5,6-trimethylene-5,6-dihydro-pyrimidine-4(3H)-on are obtained. Melting point: 138° C. to 140° C. (ethylacetate).

Analysis for C₁₃ H₁₃ ClN₂ O Calculated: C 62.78% H 5.27% N 11.26%; Found: C 62.85% H 5.42% N 11.06%.

EXAMPLE 9

A tablet of the following composition is prepared: 2-(m-chlorophenyl)-cis-5,6-trimethylene-5,6-dihydro-

    ______________________________________                                         pyrimidine-4-(3H)-on   50 mg.                                                  Amilopectine           10 mg.                                                  Crystalline cellulose  60 mg.                                                  Stearic acid           12 mg.                                                  Talcum                 13 mg.                                                  Total weight:          145 mg.                                                 ______________________________________                                    

The active ingredient and crystalline cellulose are admixed and homogenized in the above-given proportion. The corresponding quantities of stearinic acid and talcum are homogenized and passed through a 100-mesh sieve whereupon it is added to the above mixture and tableted under moderated pressure.

2-(m-chloro-phenyl)-5,6-5dimethylene-5,6-dihydro-pyrimidine-4(3H)-on prepared according to the method described in the last paragraph of Example 8, causes an inhibition of 39% during carragenin-induced oedema-test in mice, when applied in 6 mg./kg. p.o. dose.

The obtained inhibition is in the same order of magnitude as that caused by indomethacine. On the other hand the toxicity of the above compound of the formula I is LD₅₀ = 1600 mg./kg. p.o., while that of the indomethacine 33 mg/kg., p.o., i.e. the therapeutic index of our compounds is more favorable than that of indomethacine.

The compounds of the present invention thus have the same utility as indomethacine in human and animal therapy in dosages equal to or up to 50 times greater than those hitherto used for indomethacine. 

What we claim is:
 1. A compound of the formula: ##STR9## wherein (a) R¹ is methyl, cyclohexyl, phenyl, m-tolyl, p-tolyl, p-tert-butylphenyl, m-trifluoromethylphenyl, m-fluorophenyl, p-fluorophenyl, m-chlorophenyl, p-chlorophenyl, m-bromophenyl, p-bromophenyl, o-hydroxyphenyl, p-methoxyphenyl, p-nitrophenyl, benzyl, p-chlorobenzyl, m,p-dimethoxyphenyl, or o-pyridyl, R² is hydrogen and n is 2; or(b) R¹ is phenyl, p-tert-butylphenyl, m-chlorophenyl, p-chlorophenyl, p-bromophenyl or p-nitrophenyl; R² is hydrogen and n is 3; or (c) R¹ is phenyl or m-chlorophenyl, R² is hydrogen and n is 1; or (d) R¹ is methyl, R² is p-tolyl or p-ethoxyphenyl, and n is 2; or (e) R¹ is ethyl, R² is m-pyridyl or p-tolyl; and n is 2; or (f) R¹ is phenyl, R² is methyl, phenyl or p-tolyl and n is
 2. 2. The compound defined in claim 1 wherein R¹ is methyl, R² is hydrogen and n is
 2. 3. The compound defined in claim 1 wherein R¹ is cyclohexyl, R² is hydrogen and n is
 2. 4. The compound defined in claim 1 wherein R¹ is phenyl, R² is hydrogen and n is
 2. 5. The compound defined in claim 1 wherein R¹ is m-tolyl, R² is hydrogen and n is
 2. 6. The compound defined in claim 1 wherein R¹ is p-tolyl, R² is hydrogen and n is
 2. 7. The compound defined in claim 1 wherein R¹ is p-tert-butylphenyl, R² is hydrogen and n is
 2. 8. The compound defined in claim 1 wherein R¹ is m-trifluoromethylphenyl, R² is hydrogen and n is
 2. 9. The compound defined in claim 1 wherein R¹ is m-fluorophenyl, R² is hydrogen and n is
 2. 10. The compound defined in claim 1 wherein R¹ is p-fluorophenyl, R² is hydrogen and n is
 2. 11. The compound defined in claim 1 wherein R¹ is m-chlorophenyl, R² is hydrogen and n is
 2. 12. The compound defined in claim 1 wherein R¹ is p-chlorophenyl, R² is hydrogen and n is
 2. 13. The compound defined in claim 1 wherein R¹ is m-bromophenyl, R² is hydrogen and n is
 2. 14. The compound defined in claim 1 wherein R¹ is p-bromophenyl, R² is hydrogen and n is
 2. 15. The compound defined in claim 1 wherein R¹ is o-hydroxyphenyl, R² is hydrogen and n is
 2. 16. The compound defined in claim 1 wherein R¹ is p-methoxyphenyl, R² is hydrogen and n is
 2. 17. The compound defined in claim 1 wherein R¹ is p-nitrophenyl, R² is hydrogen and n is
 2. 18. The compound defined in claim 1 wherein R¹ is benzyl, R² is hydrogen and n is
 2. 19. The compound defined in claim 1 wherein R¹ is p-chlorobenzyl, R² is hydrogen and n is
 2. 20. The compound defined in claim 1 wherein R¹ is m,p-dimethoxyphenyl, R² is hydrogen and n is
 2. 21. The compound defined in claim 1 wherein R¹ is o-pyridyl, R² is hydrogen and n is
 2. 22. The compound defined in claim 1 wherein R¹ is phenyl, R² is hydrogen and n is
 3. 23. The compound defined in claim 1 wherein R¹ is p-tert-butylphenyl, R² is hydrogen and n is
 3. 24. The compound defined in claim 1 wherein R¹ is m-chlorophenyl, R² is hydrogen and n is
 3. 25. The compound defined in claim 1 wherein R¹ is p-chlorophenyl, R² is hydrogen and n is
 3. 26. The compound defined in claim 1 wherein R¹ is p-bromophenyl, R² is hydrogen and n is
 3. 27. The compound defined in claim 1 wherein R¹ is p-nitrophenyl, R² is hydrogen and n is
 3. 28. The compound defined in claim 1 wherein R¹ is phenyl, R² is hydrogen, and n is
 1. 29. The compound defined in claim 1 wherein R¹ is m-chlorophenyl, R² is hydrogen and n is
 1. 30. The compound defined in claim 1 wherein R¹ is methyl, R² is p-tolyl and n is
 2. 31. The compound defined in claim 1 wherein R¹ is methyl, R² is p-ethoxyphenyl and n is
 2. 32. The compound defined in claim 1 wherein R¹ is ethyl, R² is m-pyridyl and n is
 2. 33. The compound defined in claim 1 wherein R¹ is ethyl, R² is p-tolyl and n is
 2. 34. The compound defined in claim 1 wherein R¹ is phenyl, R² is methyl and n is
 2. 35. The compound defined in claim 1 wherein R¹ is phenyl, R² is phenyl and n is
 2. 36. The compound defined in claim 1 wherein R¹ is phenyl, R² is p-tolyl and n is
 2. 37. An antiedema composition which comprises an effective amount of the compound defined in claim 1 with at least one pharmaceutically acceptable inert carrier or diluent.
 38. A method of treating edema in animals which comprises the step of orally administering an effective amount of the compound defined in claim
 1. 